Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics.

A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 µM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 µM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 µM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF3-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC50 ranged from 1.4 to >10 µM and increased with increasing lipophilicity.

Green-, Red-, and Infrared-Emitting Polymorphs of Sterically Hindered Push-Pull Substituted Stilbenes.

The synthesis, XRD single-crystal structure, powder XRD, and solid-state fluorescence of two new DPA-DPS-EWG derivatives (DPA=diphenylamino, DPS=2,5-diphenyl-stilbene, EWG=electron-withdrawing group, that is, carbaldehyde or dicyanovinylene, DCV) are described. Absorption and fluorescence maxima in solvents of various polarity show bathochromic shifts with respect to the parent DPA-stilbene-EWGs. The electronic coupling in dimers and potential twist elasticity of monomers were studied by density functional theory. Both polymorphs of the CHO derivative emit green fluorescence (527 and 550 nm) of moderate intensity (10 % and 5 %) in polycrystalline powder form. Moderate (5 %) red (672 nm) monomer-like emission was also observed for the first polymorph of the DCV derivative, whereas more intense (32 %) infrared (733 nm) emission of the second polymorph was ascribed to the excimer fluorescence.

Pseudopeptides with aldehyde or vinylsulfone warheads: Synthesis and antiproteasomal activity.

The comparative study of new proteasome inhibitors based on salicylic acid-modified pseudo-tripeptides terminated with aldehyde or vinylsulfone is presented. We described the synthesis of 11 pairs of pseudopeptides and their properties related to the proteasome inhibition were determined. The effects of integrated amino acids (combinations of leucine, phenylalanine, tryptophan, proline, cyclohexylalanine or norleucine residues) on the activity of the proteasome were investigated. Compounds preferentially inhibited the chymotrypsin ß5-subunit of the proteasome in cell-based assays compared with the ß1- and ß2-subunits, with IC50 values in mid-nanomolar ranges being obtained for the most active members. Our comparative study demonstrated that aldehydes were able to inhibit the proteasome in cells more effectively than vinylsulfones. These results were corroborated by the accumulation of polyubiquitinated proteins in treated cells, GFP accumulation in a reporter cell line and the ability of new compounds to induce apoptotic cell death.

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE.

A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.

SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors.

A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure-activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity-activity landscape index for BChE inhibitory response values. The 'indirect' ligand-based and 'direct' protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an 'average' 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).

Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study.

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure⁻activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host⁻target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

In vitro activity of salicylamide derivatives against vancomycin-resistant enterococci.

A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacteriostatic activity against VRE (0.199-25 µM) comparable to or more potent than ampicillin and ciprofloxacin. In addition, these compounds were tested for synergistic effect with vancomycin, ciprofloxacin and tetracycline, while 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide showed the highest potency as well as synergistic activity with vancomycin against VRE 368. Screening of the cytotoxicity of the most effective compounds was performed using human monocytic leukemia THP-1 cells, and based on LD50 values, it can be stated that the compounds have insignificant toxicity against human cells.

Proline-Based Carbamates as Cholinesterase Inhibitors.

Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 µM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 µM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure-inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3'-/4'-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

Activity of selected salicylamides against intestinal sulfate-reducing bacteria.

OBJECTIVES: The aim of our work was to evaluate effect of selected salicylamides on cell viability of sulfate-reducing bacterium Desulfovibrio piger Vib-7 isolated from the human large intestine, as well as to assess antimicrobial activity and biological properties of these compounds. METHODS: Microbiological, biochemical, biophysical methods, and statistical processing of the results were used. RESULTS: An antimicrobial activity and biological properties of salicylamides against intestinal sulfate-reducing bacteria was studied. Primary in vitro screening of the synthesized selected salicylamides was performed against D. piger Vib-7. Adding 0.37-1.10 µmol.L(-1) (N-(4-bromophenyl)-5-chloro-2-hydroxybenzamide, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide, 5-chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide, 5-chloro-2-hydroxy-N-(4-nitrophenyl)benzamide and 4-chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide) caused decrease in biomass accumulation by 8-53, 64-66, 49-50, 82-90, 43-46% compared to control, respectively. The studied compounds completely inhibited the growth of D. piger Vib-7 under the effect of 30 µmol.L(-1). Moreover, addition of the compounds in the culture medium inhibited the process of dissimilation sulfate dose dependently. Treatment with salicylamides led to the bacterial growth inhibition which correlated with the level of inhibition of sulfate reduction. The data on relative survival of D. piger Vib-7 cells and cytotoxicity of salicylamides are consistent to our research in previous series of the biomass accumulation experiments. CONCLUSIONS: A significant cytotoxic activity under the influence of salicylamides was determined. These results are consistent with a data on bacterial growth and inhibition process of dissimilation sulfate. The strongest cytotoxic effect of the derivatives was observed in compounds of 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide and 5-chloro-2-hydroxy-N-(4-nitrophenyl)benzamide which showed low survival and high toxicity rates.

Synthesis and antimycobacterial and photosynthesis-inhibiting evaluation of 2-[(E)-2-substituted-ethenyl]-1,3-benzoxazoles.

A series of twelve 2-[(E)-2-substituted-ethenyl]-1,3-benzoxazoles was designed. All the synthesized compounds were tested against three mycobacterial strains. The compounds were also evaluated for their ability to inhibit photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 2-[(E)-2-(4-Methoxyphenyl)ethenyl]-1,3-benzoxazole, 2-[(E)-2-(2,3-dihydro-1-benzofuran-5-yl)ethenyl]-1,3-benzoxazole and 2-{(E)-2-[4-(methylsulfanyl)phenyl]ethenyl}-1,3-benzoxazole showed the highest activity against M. tuberculosis, M. kansasii, and M. avium, and they demonstrated significantly higher activity against M. avium and M. kansasii than isoniazid. The PET-inhibiting activity of the most active ortho-substituted compound 2-[(E)-2-(2-methoxyphenyl)ethenyl]-1,3-benzoxazole was IC50 = 76.3 µmol/L, while the PET-inhibiting activity of para-substituted compounds was significantly lower. The site of inhibitory action of tested compounds is situated on the donor side of photosystem II. The structure-activity relationships are discussed.

Synthesis and characterization of a pH-sensitive conjugate of isoniazid with Fe3O4@SiO2 magnetic nanoparticles.

The Letter describes the preparation and characterization of a conjugate of isoniazid (INH) with magnetic nanoparticles Fe3O4@SiO2 115±60 nm in size. The INH molecules were attached to the surface of nanoparticles by a covalent pH-sensitive amidine bond. The conjugate was characterized by X-ray diffraction, SEM, dynamic light scattering, IR spectroscopy and microanalysis. The conjugate released isoniazid under in vitro conditions (pH=4; 37 °C; t1/2≈115 s). In addition, the cytotoxicity of the Fe3O4@SiO2-INH conjugate was evaluated in SK-BR-3 cells using the xCELLigence system.

New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species.

Three series of salicylanilides, esters of N-phenylsalicylamides and 2-hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, in total thirty target compounds were synthesized and characterized. The compounds were evaluated against seven bacterial and three mycobacterial strains. The antimicrobial activities of some compounds were comparable or higher than the standards ampicillin, ciprofloxacin or isoniazid. Derivatives 3f demonstrated high biological activity against Staphylococcus aureus (⩽0.03µmol/L), Mycobacterium marinum (⩽0.40µmol/L) and Mycobacterium kansasii (1.58µmol/L), 3g shows activity against Clostridium perfringens (⩽0.03µmol/L) and Bacillus cereus (0.09µmol/L), 3h against Pasteurella multocida (⩽0.03µmol/L) and M. kansasii (⩽0.43µmol/L), 3i against methicillin-resistant S. aureus and B. cereus (⩽0.03µmol/L). The structure-activity relationships are discussed for all the compounds.

Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]thiazoles as cholinesterase inhibitors.

A series of novel cholinesterase inhibitors based on 2-substituted 6-fluorobenzo[d]thiazole were synthesised and characterised by IR, (1)H, (13)C and (19)F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound.

Antimycobacterial and photosynthetic electron transport inhibiting activity of ring-substituted 4-arylamino-7-chloroquinolinium chlorides.

In this study, a series of twenty-five ring-substituted 4-arylamino-7-chloroquinolinium chlorides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts and also primary in vitro screening of the synthesized compounds was performed against mycobacterial species. 4-[(2-Bromophenyl)amino]-7-chloroquinolinium chloride showed high biological activity against M. marinum, M. kansasii, M. smegmatis and 7-chloro-4-[(2-methylphenyl)amino]quinolinium chloride demonstrated noteworthy biological activity against M. smegmatis and M. avium subsp. paratuberculosis. The most effective compounds demonstrated quite low toxicity (LD50 > 20 µmol/L) against the human monocytic leukemia THP-1 cell line within preliminary in vitro cytotoxicity screening. The tested compounds were found to inhibit PET in photosystem II. The PET-inhibiting activity expressed by IC50 value of the most active compound 7-chloro-4-[(3-trifluoromethylphenyl)amino]quinolinium chloride was 27 µmol/L and PET-inhibiting activity of ortho-substituted compounds was significantly lower than this of meta- and para-substituted ones. The structure-activity relationships are discussed for all compounds.

Antibacterial and herbicidal activity of ring-substituted 2-hydroxynaphthalene-1-carboxanilides.

In this study, a series of twenty-two ring-substituted 2-hydroxynaphthalene-1­carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium marinum, M. kasasii, M. smegmatis. and M. avium paratuberculosis. The compounds were also tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 2-Hydroxy-N-phenylnaphthalene-1-carboxanilide and 2-hydroxy-N-(3-trifluoromethylphenyl)naphthalene-1-carboxamide (IC50 = 29 µmol/L) were the most active PET inhibitors. Some of tested compounds showed the antibacterial and antimycobacterial activity against the tested strains comparable or higher than the standards ampicillin or isoniazid. Thus, for example, 2-hydroxy-N-(3-nitrophenyl)naphthalene-1-carboxamide showed MIC = 26.0 µmol/L against methicillin-resistant S. aureus and MIC = 51.9 µmol/L against M. marinum, or 2-hydroxy-N-phenylnaphthalene-1-carboxamide demonstrated MIC = 15.2 µmol/L against M. kansasii. The structure-activity relationships for all compounds are discussed.

Four Slip-Stacked Arrangements, Three Types of Photophysics: Crystal Structure and Solid-State Fluorescence of 3,6-Diaryl Substituted Furo[3,4-c]furanone Polymorphs and Regioisomers.

Six symmetrical 3,6-diaryl (aryl=phenyl, 2-, 3- and 4-tolyl, 2,4- and 3,5-xylyl) substituted furo[3,4-c]furanones (DFF) were synthesized. The computational analysis, based on density functional theory, found eight possible centrosymmetrical slipped π-stack arrangements, formed according to electron repulsion minimization principle, as for previously reported for π-isoelectronic diketopyrrolopyrroles (DPP). One of these slipped stack arrangements was found to form infinite columns in the crystals of a new polymorph of parent phenyl derivative (with centre-to-centre distance CC=6.975 Å), other three types of stacks were found for 3-tolyl (CC=6.153 Å), 4-tolyl (CC=3.849 Å) and 2,4-xylyl (CC=4.856 Å) derivatives by single crystal X-ray diffractometry. All six derivatives show intense solution fluorescence in blue/green region, with a maximum driven entirely by a number and position of methyl substituents on phenyl rings. On the other hand, the solid-state fluorescence from yellow over orange to red is observed only for four derivatives and its presence/absence, spectral position and vibronic structure is driven exclusively by the slips in π-stacks (with interplanar distance always less than 3.5 Å) of almost planar DFF molecules, resulting in J-type emission, H-type excimer-like emission and H-type quenching.

Synthesis and characterization of pH-sensitive conjugate of isoniazid--methoxypoly(ethylene glycol)-b-poly(L-lysine).

The present paper deals with the preparation and characterization of a conjugate of isoniazid (INH) with the block copolymer methoxypoly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-PLL). The structure of the conjugate (mPEG-b-PLL-INH) was verified by means of (1)H NMR, GPC, infrared spectroscopy, elemental analysis and powder X-ray diffraction. The conjugate contains six l-lysine units with five INH molecules, which are attached by means of pH-sensitive amidine bond. Under in vitro conditions, the conjugate is hydrolyzed and isoniazid is released (pH 4; 37 °C; t(1/2) ≈ 10 h).

Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking.

A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'(3,4) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'(4) exhibited slightly more effective AChE inhibitors than in C'(3). Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.

Microwave-assisted synthesis of new substituted anilides of quinaldic acid.

In this study a one step method for the preparation of substituted anilides of quinoline-2-carboxylic acid was developed. This efficient innovative approach is based on the direct reaction of an acid or ester with substituted anilines using microwave irradiation. The optimized method was used for the synthesis of a series of eighteen substituted quinoline-2-carboxanilides. The molecular structure of N-(4-bromophenyl)quinoline-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. It crystallizes in the monoclinic space group with four molecules within the unit cell and the total structure of the compound can be described as "a slightly screwed boat".

Investigating the spectrum of biological activity of substituted quinoline-2-carboxamides and their isosteres.

In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial species. N-Cycloheptylquinoline-2-carboxamide, N-cyclohexylquinoline-2-carboxamide and N-(2-phenylethyl)quinoline-2-carboxamide showed higher activity against M. tuberculosis than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonyl)quinoline and 1-(2-naphthoyl)pyrrolidine expressed higher activity against M. kansasii and M. avium paratuberculosis than the standards isoniazid or pyrazinamide. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC(50) value of the most active compound N-benzyl-2-naphthamide was 7.5 µmol/L. For all compounds, the structure-activity relationships are discussed.